Screening Method for Inhibitors of Multidrug-Resistance Transporters (Case 2079)

Principal Investigator:


Jeffrey Morgan, PhD, Professor

Department of Bio Med Molecular Pharmacology, Physiology and Biotechnology

Brown University

Providence, RI


Brief Description:


Multidrug-resistance transporters (MDR) are protein pumps that are up regulated in diseased cells such as those in cancer patients.  These proteins actively pump out beneficial therapeutics making the cells resistant to medical treatment.  There is a strong clinical need to discover drugs that can inhibit these pumps and be co-delivered with therapeutics, while not adversely affecting the uptake and transport of the therapeutics.


Currently, there are three primary methods used to screen drug catalogues for MDR inhibition: monolayer efflux studies of radiolabeled compounds in transwells, drug-stimulated ATPase activity, and inhibition of calcein uptake assays.  Each assay uses a monolayer of cells and is capable of measuring inhibition of MDR, but it is unclear if these methods can adequately predict in vivo efficacy.  Drug transport in the monolayer, two-dimensional (2D) systems does not accurately replicate all of the complexity and biology of the barriers found in a three-dimensional (3D) multi-cell layer environment.  For example, mass transport limitations, which are of particular importance to drug screening and are major transport barriers in 3D systems, are missing from the monolayer, 2D system.  Although assay methods exist to quantify 3D transport, there are major limitations.  These include a lack of information about the entire micro-tissue, time-consuming protocols, and the inability to apply higher throughput analyses due to a reliance on historical processing and contact autoradiography.  Furthermore, current methods only offer an average activity or fluorescence data and provide no information about drug penetration, an important factor in drug screening for MDR inhibition. 


The invention offered here overcomes current limitations by introducing a high throughput in vitro drug screening method that can perform more relevant quantification of MDR inhibition in 3D micro-tissues.  This innovative method measures the uptake and transport through scaffold-free, 3D multi-cellular spheroids that mimic the in vivo environment of solid tumors, which these drugs target.  The novel method reveals significantly more drug information about overall uptake, transport, localization/destination in tissue, penetration time to center of tissue, and drug concentration (pharmacologic relevance) at center of tissue.  Through the calculation of quantitative diffusion, uptake, efflux, and penetration data this technology is able to generate a mathematical model that yields a complete 3D reconstruction of the concentration profile as a function of time.


This unique screening method can be used to find new and more effective efflux pump inhibitors, critical for the treatment of cancer, and can be used to quickly assess the bioavailability of numerous new drugs.  Comparative drug studies can be completed in a high throughput manner.  More broadly, the new method allows researchers to measure transport parameters and the concentration gradient of any drug, nutrient, metabolite, or ion that is fluorescently labeled.


Two primary markets include pharmaceutical therapeutics and drug development tools with applications in the medical fields of drug discovery and development, oncology, molecular pharmacology and drug delivery.




US patent application 13/623,599 is pending

Patent Information:
For Information, Contact:
Brown Technology Innovations
350 Eddy Street - Box 1949
Providence, RI 02903
Jeffrey Morgan
Anubhav Tripathi
Toni-Marie Achilli (formerly Ferrucc
Stephanie Mccalla
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